This competing renewal uses quantitative structural MRI to address several fundamental questions regarding the status of morphometric brain alterations in schizophrenia and bipolar affective disorder. The initial grant gathered samples of subjects with schizophrenia, and bipolar disorder as well as healthy control subjects. The current proposal focuses on six major inter-related questions spanning the origin and progression of the brain alterations, whether they are inherited, and their relation to symptom classes and to disease outcome. The major questions concern the following: 1. Which brain changes in schizophrenia are specific to the disorder, as opposed to shared with psychotic bipolar disorder. 2. Is there evidence of neuro-developmental brain changes in schizophrenia, and if so do these differ from those seen in psychotic bipolar disorder. 3. Are brain changes in schizophrenia progressive in some or all patients. 4. Are local brain alterations in schizophrenia related to clinical symptoms. 5. Do local brain alterations in schizophrenia predict social and occupational functioning 5 years later. 6. Do the types of brain changes seen in schizophrenia also occur in some or all of their siblings. There are several strengths to the application. Many of the patients and controls derive from large, well-characterized populations who are participants in ongoing, funded studies of the genetics of schizophrenia and bipolar disorder, or a longitudinal study of normal aging who have already been MRI scanned using identical parameters. These subjects' origin in existing studies helps ensure ease of tracking, subject retention and willingness to be re-MRI scanned. This latter is important as a proportion of patients will be re-scanned 5 years after their initial, existing MRI studies. The investigators have developed state-of-the-art software methods for MRI display and measurement and have expertise in sophisticated, reliable volumetric quantification of many brain regions, including complex cortical areas. This latter ability is important, as preliminary evidence suggests that these same brain regions are disproportionately affected by the disorder. Preliminary data gathered with our new MRI methods show feasibility, and will allow us to further study these cortical areas, providing supportive evidence for a hypothesis of particular reduction of volume in, and disruption of normal asymmetries within heteromodal association cortical gray matter regions in schizophrenia. The overall project will allow a systematic investigation of related multi-system neural deficits. The circumstances of the proposed project are exceptional, in that they offer an opportunity to address a series of important and wide-ranging questions regarding brain abnormalities in schizophrenia and bipolar disorder in an integrated manner. The combination of advantages referred to above will help us to provide answers to hypotheses ranging from the level of inherited abnormalities to that of disease outcome.